Screening of differentially expressed protein kinases in bone marrow endothelial cells and the protective effects of the p38a inhibitor SB203580 on bone marrow in liver fibrosis

Abstract

Hematological abnormalities are frequently observed in patients with liver cirrhosis (LC). A previous study demonstrated that the apoptosis and damage of endothelial cells could cause the hematological abnormalities in LC. Protein kinases are one of the most important factors that regulate cell behavior, and are potential therapeutic targets for the treatment of a number of diseases. In a previous study, whole genome profiling was used to identify differentially expressed genes in human bone marrow endothelial cells treated with serum from 26 patients with LC. From this data set, the present study identified 14 differentially expressed kinase genes in human bone marrow endothelial cells in LC from the microarray data, including p38a, AKT1 and PDK1. Pathway analysis revealed that these kinase genes were enriched in certain important LC-associated pathways (e.g. MAPK and WNT signaling pathway). Literature mining revealed that p38a was associated with bone marrow apoptosis; therefore, p38a and its inhibitor, SB203580, were selected as potential therapeutic targets in the present study. The results of hematoxylin-eosin and Masson's trichrome staining of livers from a rat model of liver fibrosis (LF) that underwent ligation of the bile duct demonstrated that SB203580 reduced the degree of LF. In addition, SB203580-treated rats with LF demonstrated a significantly higher number of platelets when compared with the untreated group. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis indicated that apoptosis of bone marrow tissue in rats with LF was inhibited by SB203580. In addition, the results from the immunohistochemical analysis demonstrated that SB203580 reduced the expression of von Willebrand factor and caspase 3 in the bone marrow of rats with LF. In conclusion, the results from the present study indicate that the p38a kinase inhibitor, SB203580, may exhibit a protective effect on bone marrow tissues in rats with LF. This suggests that protein kinases and their inhibitors may present novel therapeutic strategies for the treatment of hematological abnormalities in patients with LC.

Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management

“…TGF-β has a significant role in metastasis and angiogenesis of cancer cells which could be inhibited by a small molecule inhibitor, LY2109761 [ 116 ]. LY2109761 has an inhibitory impact on the expression of HSP47 in rat precision-cut liver slices which is increased by the prolongation of incubation periods [ 117 ].…”